Down syndrome and Inflammation ((EXTENDED VERSION)) Joaquin Espinosa,executive director of the Crnic Institute for Down syndrome, discusses the inner workings of cells in people with the genetic mutation known as Down syndrome. His findings may explain some common characteristics of Down syndrome, such as shorter stature, cognitive challenges, protection from some cancers, and increased risk of pneumonia and Alzheimer’s. Espinosa’s lab used Boulder’s Somalogic protein analysis tool to inspect thousands of the different proteins our bodies make. The lab discovered a few hundred proteins that are noticeably different for people with Down syndrome. These proteins do not specifically influence height or how to take a test. Instead, they reveal an out-of-balance immune system. PRODUCER – Shelley Schlender

Joaquin Espinosa: I’m Joaquin Espinosa. I’m a professor of pharmacology at the University of Colorado Anschutz Medical Campus. I’m also the executive director of the Linda Crnic Institute for Down Syndrome at the Anschutz Medical Campus.

Shelley Schlender: In your lab you work on cancer and Down syndrome.

Joaquin Espinosa: Correct. I have two research teams. One of them is focused on cancer research. One of them on Down syndrome but as we may be able to talk later there are connections between these two conditions.

Shelley Schlender: Do you know some people with Down syndrome.

Joaquin Espinosa: I do.

Shelley Schlender: What are they like?

Joaquin Espinosa: Oh they are fascinating. First of all no two people are the same. With or without the syndrome, so I don’t want to generalize about people with Down Syndrome. But there are some patterns, some qualities that are common among people with Down syndrome. They’re very kind. They’re very accepting very loving. So they’re really a great presence.

Shelley Schlender: Yes I’ve heard that many times that people with Down syndrome there’s a way that in their presence they remind all of us of some of the most magical and special parts of being alive and being with other people.

Joaquin Espinosa: Yes they have a joy of life. They are also very emotionally intelligent. I think they can perceive even ahead of yourself your emotional state. They can sense if you’re stressed or if you are happy and they can, interact in that way with you reading you at the emotional level very well.

DOWN SYNDROME —ALZHEIMER’S—AUTOIMMUNE DISEASES—CANCER

Shelley Schlender: And at the same time people with Down syndrome, by the age of 40, most of them will have Alzheimer’s disease; by the age of 40, most will have some kind of serious autoimmune disorder, and they’re also prone to infectious diseases, and they’re prone to some kinds of cancers but not others.

Joaquin Espinosa: Yeah — let me elaborate a little bit on that. The Alzheimer’s piece, first of all, yes people with Down syndrome are the largest population with a genetic predisposition to early onset Alzheimer’s disease. And by the age of 40 most of them had the signs of the pathology in the brain, but not necessarily the dementia–the true manifestation of the disease. It may take another 20 years or so for that dementia to develop. And they have a lot of variability, and some of them despite the fact that they had that brain pathology do not become demented until their 70s. So studying people with Down syndrome can really reveal how to modulate the progression of Alzheimer’s disease. It is also true that people with Down syndrome are highly predisposed to autoimmune conditions. Things like Hashimoto’s Hypothyroidism, when the immune system attacks the thyroid gland, celiac disease, rheumatoid arthritis, type 1 diabetes. So a whole range of conditions. The Cancer Connection is fascinating. On one hand, they are protected from most solid malignancies. And what I mean by these is tumours of solid tissues, like breast cancer, prostate cancer, colon cancer, liver cancer–much reduced rates of those.On the other hand they have higher rates of leukemias, the malignancies of the blood cells. So there is something very interesting going on there.

Shelley Schlender: They get some kinds of cancers they don’t get other kinds. They’re more prone to the placquing of Alzheimer’s disease though some may not show signs of dementia till a later age. They are definitely more prone to autoimmune diseases. Now you did a study that involved an extensive look at proteins and how proteins expressed in the bodies of people with the genetic condition we call Down Syndrome. What is special about a protein study why would you study proteins.

5,000 PROTEINS—IMMUNE SYSTEM “HYPERACTIVATION”

Joaquin Espinosa: So we did two studies and they’re related. One was looking at the proteins in the blood. Let me remind you that our genetic information goes from DNA which is packaged in our chromosomes. It produces a molecule called RNA and then the RNA then becomes translated into proteins so more or less, for every gene in the human genome and there are like 20,000 genes you would find a protein somewhere or another in the body. So if you want to study the genetic information, the genetic makeup of an individual, or any organism, looking at collections of proteins could be very informative.

Shelley Schlender: In studying proteins do proteins do all the jobs in the body.

Joaquin Espinosa: Not all of them but many, if not most of them.

Shelley Schlender: So by studying proteins in the body you can get some ideas of what kind of jobs is the body doing what kind of jobs might it be doing too much and what kind of jobs might it be doing too little.

Joaquin Espinosa: Correct.

Shelley Schlender: So you studied the proteins between people with Down syndrome and also people who don’t have Down syndrome. Where were the variations.

Joaquin Espinosa: We looked at almost 5,000 proteins in the blood of people with and without Down syndrome, and we found about 300 that were very different, meaning they were significantly elevated or significantly depleted in people with Down syndrome, and about half of those proteins had to do the immune system.

Shelley Schlender: The immune system. Is that what people have normally thought is the area of a person with Down syndrome that is different from other people.

Joaquin Espinosa: It was noted here and there in the literature that people with Down syndrome have differences in the immune system but nobody had done this unbiased analyses of thousands of proteins that would place the immune system at the top of the chart as the top category of what is different in people with Down syndrome.

Shelley Schlender: When people think about Down syndrome, they usually think about somebody who doesn’t do as well on standardized school tests–yet it’s the immune system that you found is different.

Joaquin Espinosa: Correct. And everything that we talked about–the different disease spectrum, people with Down syndrome having more Alzheimer’s. less solid tumors, more leukemia but also the cognitive aspects. All of it could potentially be explained by these differences in the immune system. Let me elaborate a little bit on the role of the immune system in the brain, since you brought that up. Yes people with Down syndrome have cognitive differences. About 15 percent of the cells in our brains are immune cells that are called the microglia. These are cells that are sitting in our brains to protect the neurons and other cells in the brain from infections. In Down syndrome, the microglia, the immune cells of the brain, become hyperactive. They produce toxic compounds that will basically poison your brain. So even the cognitive aspect of Down syndrome could be explained by a hyperactivation of the immune system.

Shelley Schlender: You just said hyperactivation, meaning that it looks like the immune system is working too hard. Working so hard that it’s doing some wrong things in people with Down syndrome.

Joaquin Espinosa: Correct. The immune system has many branches. It’s not the same branch of the immune system that we use to fight off a virus than it is to fight off a bacterial infection. So what we’re seeing is a particular aspect of the immune system involving the viral defense and the tumor defense, called the interferon response, because it interferes with viral replication. In Down syndrome that is hyperreactive. But when you’re doing too much of something, even if it were to be a good thing, of course you can see exhaustion and you can see it eventually wear out the system. So we like to say that the Immune system of people with Down syndrome is generally out of balance.

Shelley Schlender: Do you mean that there’s too many of these immune cells doing things, or do you mean the immune cells are exhausted and they’re working too hard trying to do things that they really don’t need to be so worried about.

Joaquin Espinosa: We see both, which is some type of immune cells that people with Down syndrome have more of and they are more active. For example the cells that are involved in fighting off tumors. Now the cells that are involved in fighting off tumores are the same cells that could cause autoimmunity because rather than attacking a tumor they start attacking a healthy tissue. There you go you have an autoimmune disease.

Shelley Schlender: Meaning that the cells started out, we hope, fighting something that needed to be fought in the body. But then it got confused and it said Well this other cell looks a little bit like the cell I was fighting. So maybe I should fight it too. And it happens to be a cell that’s part of our body that is fighting now.

Joaquin Espinosa: Correct. When the vigilantes in your body are hyperactive the chances of making a mistake increase. And that’s what we’re seeing. But there are also other aspects of the immune system that are depleted–the immune system is out of balance. Some parts are too active. Some parts are weakened.

Shelley Schlender: In the case of somebody with Down syndrome your research indicates that they may have the dial turned up to high on attacking cells that, to the immune system, like similar to viruses . . . including body cells that look somewhat similar to viruses. But on the other hand if somebody with Down syndrome gets a bacterial infection, they’re prone to get really sick from it.

Joaquin Espinosa: Absolutely correct that antibacterial defenses in people with Down syndrome are diminished. In fact bacterial pneumonia of the lung, you know, lung pneumonia, is the top cause of mortality among people with Down syndrome. Few people know that. So this is a main concern for us, and an area of intensive research. How can we normalize the immune system so that we tone down the aspects that are hyperactive and at the same time we build up the antibacterial defenses that may help these individuals fight off the pneumonia.

DRUGS & OTHER INVESTIGATIONS FOR “TAMING” IMMUNE SYSTEM

Shelley Schlender: Well how about using some of the standard immunotherapies such as using a steroid drug to just suppress the whole immune system, etc.

Joaquin Espinosa: Steroid Drugs will not produce the type of rebalancing that we would like to achieve. But there are other approved drugs used for some auto-inflammatory conditions like rheumatoid arthritis for example. These drugs are called JAK inhibitors (Jakinibs, or Janus Kinase Inhibitors) which we think will do a better job than just a corticosteroid. So we are testing these drugs in animals models. We have mouse models of Down syndrome, that is mice that have an extra chromosome, just like people with Down syndrome do. But also we know now of some individuals with Down syndrome that have taken these drugs for some of their autoimmune conditions and they’re seeing benefits. So we are also planning on eventually doing the appropriate clinical trial to test these immune therapies that could bring back the immune system to a state of balance.

Shelley Schlender: Are you envisioning that a course of treatment with one of these drugs could get the immune system to a place where can take care of itself. Or are you thinking that this would be a lifelong using of a drug or a nutritional approach or something, that would help rebalance the system in an ongoing way.

Joaquin Espinosa: I don’t think it would be a treatment that you would take for only a few weeks or a few months and then you kind of stop it. This is more like a chronic inflammatory condition. So examples will be rheumatoid arthritis or autoimmune conditions like celiac disease. So you have to be on a chronic treatment. Now when you do a long term treatment of course the concern is for undesired side effects appear if you’re going to tone down the immune system. You want to make sure you don’t do it too much. Otherwise you will increase the risk of some viral infections. To give an idea we have people with rheumatoid arthritis that have been taking these immune therapies for 20 years now and they continue to take these pills everyday. So it is possible to envision that people with Down syndrome would be on some kind of immune therapy from an early age. How early. We don’t know the research will have to be done and then continue with this for lifelong benefits. You did mention something about changes in the nutrition this is something that we’re very interested in. Are there types of anti inflammatory diets that could help people with Down syndrome. We hope so. I mentioned to you that people with Down syndrome are more likely to develop celiac disease So in those with a diagnosis of celiac disease. Of course a gluten free diet will have profound benefit.

Shelley Schlender: Are there any other nutritional interventions or exercise interventions that you think might be helpful.

Joaquin Espinosa: In terms of nutrition where we’re paying attention to everything that people with Down syndrome have been taking. There are a number of dietary supplements that families have adopted here and there. And as part of our research we have a cohort study of the population with Down syndrome where people with Down syndrome and their relatives provide us with biological samples but also with medical information and lifestyle information. So we’re recording all these data and if any of these dietary supplements were to have a benefit on the immune system we’ll probably pick it up during the course of this study. We’re not there yet. We have almost 500 participants in this study. To do this type of research we’ll probably need thousands of participants to have enough who are taking a supplement versus enough who or not taking the supplement to be able to do that research.

Shelley Schlender: How about things like how much carbohydrate does someone eat compared to how much fat compared to how much protein.

Joaquin Espinosa: We’re looking at the metabolism of people with Down syndrome in fact we published a paper last year and we have another one in preparation where again we looked at the blood and the plasma, and we measured various kinds of fats, carbohydrate, amino acids. And there are some differences in metabolism. Whether those differences then can be interpreted in a modification to the diet that will help the immune system, it’s early days to get there, but there is evidence that people with Down syndrome may metabolize certain nutrients in a different way.

Shelley Schlender: And how about hormones. Did your test look at insulin levels? Cortisol levels?

DOWN SYNDROME – HIGH LEPTIN — SLEEP APNEA

Joaquin Espinosa: We have looked at several hormones. Not all of them. We’ve found that a hormone called leptin, which is involved in energy metabolism but also control of appetite, is disregulated in people with Down syndrome who have obstructive sleep apnea. So it turns out that about half of people with Down syndrome have a sleep disturbance where they have, basically a problem with airflow during the night and they wake up many times during the night. There are some treatments that one could do for such as C-Pap. So we have noticed in our study that those that have obstructive sleep apnea have deregulated leptin levels. It has been noted in the literature in typical people that if you have obstructive sleep apnea, your metabolism may change and you may actually put on weight. So that is just one example of how one of the co-morbidities of Down syndrome, in this case a sleep disturbance, can then impact the metabolism and body weight.

Shelley Schlender: Or Vice versa. It’s not clear whether the disregulation of leptin is leading to more sleep apnea or the other way around. But you also said disregulation–does that mean that people tend to have higher levels of this hormone called leptin, or do they have levels of the leptin that are too low? How is leptin dis-regulated.

Joaquin Espinosa: Leptin is elevated in the plasma of people with Down syndrome and obstructive sleep apnea. But what happens when you are constantly exposed to high levels of a hormone, you may become desensitized to it and you may acquire what is called leptin resistance. Yes you have more of it in the blood, but actually you respond less to it. You have become desensitized. So that’s why I use the word disregulation.

Shelley Schlender: That’s similar to insulin resistance where somebody has high levels of insulin but their cells can’t hear the signal. Do people with Down syndrome tend to have high levels of insulin as well?

DOWN SYNDROME TYPE 1 DIABETES

Joaquin Espinosa: No. What we see in down syndrome is is more of that type 1 diabetes the autoimmune juvenile diabetes, where the new system makes some mistake and attacks the beta cells in the pancreas that produce insulin. So that is why we see more of it– with that being said this is not a highly prevalent condition in Down syndrome.

Shelley Schlender: And so the leptin is usually high but the insulin is not usually at an unusual level. Well it sounds like you’re finding out a lot of fascinating information that may also inform people about other diseases such as Alzheimer’s such as cancer formation, such as immune system activity for protecting people against pneumonia.

DOWN SYNDROME FEWER ALLERGIES

Joaquin Espinosa: Correct. So this extra chromosome–chromosome 21 has about 200 genes that people with Down syndrome have an extra copy of — a 3rd copy — clearly it’s regulating human biology in myriad ways, predisposing to some conditions or protecting from others. So it gives us a unique discovery platform to understand human biology and human disease. And we talked about the major examples Alzheimer’s cancer autoimmune conditions but there are many other conditions that are either more elevated or less frequent in people with Down syndrome. For example, people with Down syndrome have more autism, more epilepsy, but they have less allergic sensitization–fewer allergies of a certain type and I could go on and on. So this small more chromosome is really loaded with a treasure of information about human biology or human disease.

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